This program takes a broad approach to gain understanding of human natural killer (NK) cell biology. The varied scientific expertise represented by the units of the program will concentrate on two goals. Firstly, collaboration between the Units will elucidate pathways controlling human NK cell receptor expression and signaling and establish their role in NK cell function. Lanier will define CDS's role on human NK cells and characterize novel NK cell receptor signaling pathways, with emphasis on NK cell activation. Parham will characterize NK cell receptor polymorphisms that influence receptor expression (both at the protein and promoter level) and test their functional effects. Another unit will explore membrane traffic pathways that influence NK cell receptor function and determine how signaling pathways and receptor polymorphisms affect these pathways. Together the units will focus on molecular pathways that influence the balance between signals coming from activating and inhibitory receptors, a balance that is central to NK cell function. The program's second goal is to establish the clinical importance of molecular mechanisms of NK cell function. Nixon and Michaelsson will study the role of NK cells during HIV infection. Patterns of NK cell subset expression and receptor usage during the course of disease and its treatment will be defined. The program's principal investigator (Brodsky) has expertise in analyzing membrane traffic pathways in lymphoid cells. While new to NK cells, Brodsky's program provides a focus for the other units through the application of cell biology to define pathways implicated by the immunology and genetics. Parham and Lanier are experts in the NK cell field and have a history of successful collaboration. The program's personnel will meet regularly and will benefit from cores dedicated to microscopy and to monoclonal antibody production, as well as shared transfection equipment necessary for studying human NK cell function. Overall, this program will link basic mechanistic studies on human NK cells to the functions of these cells in HIV infection.